The general aim of the proposed research is to evaluate the contribution and mechanism of paraoxonase (PON1) genotypic and phenotypic variation (PON1 status) in risk and progression of carotid artery disease (CAAD). We propose to study moderately affected individuals currently being enrolled in a longitudinal, 3-year magnetic resonance imaging (MR) study to evaluate components of MR image as predictors of CAAD progression. We will study the role of PON1 in CAAD progression in this cohort. We will also collect age-, sex-, race-, and hospital- matched controls, to test hypotheses related to the presence or absence of CAAD. We plan to consider the complex genetic architecture of both vascular disease and PON1 effects in vascular disease. In addition to evaluating known paraoxonase (PON1) polymorphisms, we will evaluate PON1 hydrolysis phenotypes. We have shown that these intervening phenotypes can be superior to known genotypes in CAAD prediction. We will also evaluate PON1 polymorphisms that we have recently detected and shown to affect PON1 expression, as well as consider haplotype effects. The specific aims are to: 1) test for PON1 effects in CAAD progression evaluated by 3 year magnetic resonance image follow-up of percent lumen stenosis; 2) test for PON1 effects in moderate CAAD vs. control prediction, including independence of PON1 from traditional cardiovascular risk factors; and 3) evaluate the possible mechanisms of PON1's association with carotid artery disease, specifically PON1's relationship with the susceptibility of LDL to oxidation, variation in LDL density, and serum homocysteine level.